Solid state forms of netarsudil mesylate

ABSTRACT

Disclosed are solid state forms of Netarsudil mesylate, processes for preparation thereof, uses thereof, and pharmaceutical compositions thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Nos.62/453,764 filed Feb. 2, 2017 and 62/469,214 filed Mar. 9, 2017, whichare hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to solid state forms of Netarsudilmesylate, processes for preparation thereof and pharmaceuticalcompositions thereof.

BACKGROUND OF THE INVENTION

Netarsudil, has the chemical name Benzoic acid, 2,4-dimethyl-,(4-((1S)-1-(aminomethyl)-2-(6-isoquinolinylamino)-2-oxoethyl)phenyl)methylester. Netarsudil has the following chemical structure:

Netarsudil ophthalmic solution (Rhopressa®) 0.02% was approved for thelowering of elevated intraocular pressure (IOP) in patients withopen-angle glaucoma or ocular hypertension by the FDA.

Netarsudil and process for preparation thereof are known fromWO2010/126626. In said process Netarsudil is separated from a racemicmixture by chiral chromatography or salt formation one step before thefinal API.

The dimesylate salt of Netarsudil is disclosed in WO2014/144781 andprocess for preparation thereof is disclosed in U.S. Pat. No. 9,643,927.

Polymorphism, the occurrence of different crystal forms, is a propertyof some molecules and molecular complexes. A single compound, likeNetarsudil, may give rise to a variety of polymorphs having distinctcrystal structures and physical properties like melting point, thermalbehaviors (e.g. measured by thermogravimetric analysis—“TGA”, ordifferential scanning calorimetry—“DSC”), powder X-ray diffraction(XRPD) pattern, infrared absorption fingerprint, Raman absorptionfingerprint, and solid state (¹³C-) NMR spectrum. One or more of thesetechniques may be used to distinguish different polymorphic forms of acompound.

Different salts and solid state forms (including solvated forms) of anactive pharmaceutical ingredient may possess different properties. Suchvariations in the properties of different salts and solid state formsand solvates may provide a basis for improving formulation, for example,by facilitating better processing or handling characteristics, improvingthe dissolution profile, or improving stability (polymorph as well aschemical stability) and shelf-life. These variations in the propertiesof different salts and solid state forms may also provide improvementsto the final dosage form, for instance, if they serve to improvebioavailability. Different salts and solid state forms and solvates ofan active pharmaceutical ingredient may also give rise to a variety ofpolymorphs or crystalline forms, which may in turn provide additionalopportunities to use variations in the properties and characteristics ofa solid active pharmaceutical ingredient for providing an improvedproduct.

Discovering new salts, solid state forms and solvates of apharmaceutical product can provide materials having desirable processingproperties, such as ease of handling, ease of processing, storagestability, and ease of purification or as desirable intermediate crystalforms that facilitate conversion to other salts or polymorphic forms.New salts, polymorphic forms and solvates of a pharmaceutically usefulcompound can also provide an opportunity to improve the performancecharacteristics of a pharmaceutical product (dissolution profile,bioavailability, etc.). It enlarges the repertoire of materials that aformulation scientist has available for formulation optimization, forexample by providing a product with different properties, e.g., adifferent crystal habit, higher crystallinity or polymorphic stabilitywhich may offer better processing or handling characteristics, improveddissolution profile, or improved shelf-life. Accordingly, there is aneed for solid state forms of Netarsudil and salts thereof.

SUMMARY OF THE INVENTION

The present disclosure relates to solid state forms of Netarsudil andsalts thereof, in particular Netarsudil mesylate, to processes forpreparation thereof, and to pharmaceutical compositions comprising thesesolid state forms.

The present disclosure also provides uses of the solid state forms ofNetarsudil and salts thereof for preparing other solid state forms ofNetarsudil, Netarsudil salts and solid state forms thereof.

In another embodiment, the present disclosure encompasses the abovedescribed solid state forms of Netarsudil and salts thereof for use inthe preparation of pharmaceutical compositions and/or formulations,preferably for the treatment of glaucoma or ocular hypertension.

In another embodiment the present disclosure encompasses the use of theabove described solid state form of Netarsudil and salts thereof for thepreparation of pharmaceutical compositions and/or formulationscomprising Netarsudil as a single API or in combination with otheractive ingredients.

The present disclosure further provides pharmaceutical compositionscomprising the solid state forms of Netarsudil and salts thereofaccording to the present disclosure.

In yet another embodiment, the present disclosure encompassespharmaceutical formulations comprising the above described solid stateforms of Netarsudil and salts thereof and at least one pharmaceuticallyacceptable excipient, preferably for local treatment in a form ofophthalmic solution.

The present disclosure encompasses processes to prepare saidpharmaceutical formulations of Netarsudil and salts thereof comprisingcombining the above solid state forms and at least one pharmaceuticallyacceptable excipient.

The solid state forms as defined herein, as well as the pharmaceuticalcompositions or formulations of the solid state form of Netarsudil andsalts thereof, can be used as medicaments, particularly for thetreatment of glaucoma or ocular hypertension.

The present disclosure also provides methods of treating glaucoma orocular hypertension, comprising administering a therapeuticallyeffective amount of Netarsudil and salts thereof of the presentdisclosure, or at least one of the above pharmaceutical compositions orformulations, to a subject suffering from glaucoma or ocularhypertension, or otherwise in need of the treatment.

The present disclosure also provides uses of the solid state forms ofNetarsudil and salts thereof of the present disclosure, or at least oneof the above pharmaceutical compositions or formulations for themanufacture of a medicament for treating glaucoma or ocularhypertension.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a powder X-ray diffraction pattern (“powder XRD” or “XRPD”)of Netarsudil mesylate form N1 obtained in Example 1.

FIG. 2 shows a powder X-ray diffraction pattern of Netarsudil mesylateform N2 obtained in Example 2.

FIG. 3 shows a powder X-ray diffraction pattern of Netarsudil mesylateform N3 obtained in Example 3.

FIG. 4 shows a powder X-ray diffraction pattern of Netarsudil mesylateform N4 obtained in Example 6.

FIG. 5 shows a powder X-ray diffraction pattern of Netarsudil mesylateform N5 obtained in Example 7.

FIG. 6 shows a powder X-ray diffraction pattern of Netarsudil mesylateform N6 obtained in Example 8. The strong peak at about 28.5 degrees(marked with Si) is attributed to silicon powder added as an internalstandard.

FIG. 7 shows a powder X-ray diffraction pattern of Netarsudil mesylateform N7 obtained in Example 9.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure relates to solid state forms of Netarsudil andsalts thereof, in particular Netarsudil mesylate, processes forpreparation thereof and pharmaceutical compositions comprising saidsolid state forms.

The solid state forms of Netarsudil and salts thereof according to thepresent disclosure may have advantageous properties selected from atleast one of: chemical or polymorphic purity, flowability, solubility,dissolution rate, bioavailability, morphology or crystal habit,stability—such as chemical stability as well as thermal and mechanicalstability with respect to polymorphic conversion, stability towardsdehydration and/or storage stability, a lower degree of hygroscopicity,low content of residual solvents and advantageous processing andhandling characteristics such as compressibility, or bulk density.

A crystal form may be referred to herein as being characterized bygraphical data “as depicted in” a Figure. Such data include, forexample, powder X-ray diffractograms and solid state NMR spectra. As iswell-known in the art, the graphical data potentially providesadditional technical information to further define the respective solidstate form (a so-called “fingerprint”) which can not necessarily bedescribed by reference to numerical values or peak positions alone. Inany event, the skilled person will understand that such graphicalrepresentations of data may be subject to small variations, e.g., inpeak relative intensities and peak positions due to factors such asvariations in instrument response and variations in sample concentrationand purity, which are well known to the skilled person. Nonetheless, theskilled person would readily be capable of comparing the graphical datain the Figures herein with graphical data generated for an unknowncrystal form and confirm whether the two sets of graphical data arecharacterizing the same crystal form or two different crystal forms. Acrystal form of Netarsudil and salts thereof referred to herein as beingcharacterized by graphical data “as depicted in” a Figure will thus beunderstood to include any crystal forms of the Netarsudil and saltsthereof, characterized with the graphical data having such smallvariations, as are well known to the skilled person, in comparison withthe Figure.

A solid state form (or polymorph) may be referred to herein aspolymorphically pure or substantially free of any other solid state (orpolymorphic) forms. As used herein in this context, the expression“substantially free of any other forms” will be understood to mean thatthe solid state form contains about 20% or less, about 10% or less,about 5% or less, about 2% or less, about 1% or less, or about 0% of anyother forms of the subject compound as measured, for example, by XRPD.Thus, solid state of Netarsudil and salts thereof, described herein assubstantially free of any other solid state forms would be understood tocontain greater than about 80% (w/w), greater than about 90% (w/w),greater than about 95% (w/w), greater than about 98% (w/w), greater thanabout 99% (w/w), or about 100% (w/w) of the subject solid state form ofNetarsudil and salts thereof. Accordingly, in some embodiments of thedisclosure, the described solid state forms of Netarsudil and saltsthereof may contain from about 1% to about 20% (w/w), from about 5% toabout 20% (w/w), or from about 5% to about 10% (w/w) of one or moreother solid state forms of the same Netarsudil and salts thereof.

As used herein, unless stated otherwise, XRPD peaks reported herein arepreferably measured using CuK α radiation, λ=1.5418 Å.

As used herein, the term “isolated” in reference to solid state forms ofNetarsudil and salts thereof, of the present disclosure corresponds tosolid state forms of Netarsudil and salts thereof that are physicallyseparated from the reaction mixture in which it is formed.

A thing, e.g., a reaction mixture, may be characterized herein as beingat, or allowed to come to “room temperature”, often abbreviated “RT.”This means that the temperature of the thing is close to, or the sameas, that of the space, e.g., the room or fume hood, in which the thingis located. Typically, room temperature is from about 20° C. to about30° C., or about 22° C. to about 27° C., or about 25° C. A process orstep may be referred to herein as being carried out “overnight.” Thisrefers to a time interval, e.g., for the process or step, that spans thetime during the night, when that process or step may not be activelyobserved. This time interval is from about 8 to about 20 hours, or about10 to about 18 hours, typically about 16 hours.

The term “solvate”, as used herein and unless indicated otherwise,refers to a crystal form that incorporates a solvent in the crystalstructure. When the solvent is water, the solvate is often referred toas a “hydrate.” The solvent in a solvate may be present in either astoichiometric or in a non-stoichiometric amount.

The crystal hydrate indicated by single crystal analysis or by wateranalysis by Karl Fischer (KF) titration or by TGA analysis of thisproduct is believed to have been produced as a result of waterintroduced from the atmosphere in which this material was processed, orby traces of water present in the solvents that were in contact with thematerial, or a combination of these factors.

The amount of solvent employed in a chemical process, e.g., a reactionor crystallization, may be referred to herein as a number of “volumes”or “vol” or “V.” For example, a material may be referred to as beingsuspended in 10 volumes (or 10 vol or 10V) of a solvent. In thiscontext, this expression would be understood to mean milliliters of thesolvent per gram of the material being suspended, such that suspending 5grams of a material in 10 volumes of a solvent means that the solvent isused in an amount of 10 milliliters of the solvent per gram of thematerial that is being suspended or, in this example, 50 mL of thesolvent. In another context, the term “v/v” may be used to indicate thenumber of volumes of a solvent that are added to a liquid mixture basedon the volume of that mixture. For example, adding methyl tert-butylether (MTBE) (1.5 v/v) to a 100 ml reaction mixture would indicate that150 mL of MTBE was added.

As used herein, the term “reduced pressure” refers to a pressure ofabout 10 mbar to about 50 mbar.

As used herein, and unless stated otherwise, the term “anhydrous” inrelation to crystalline Netarsudil and salts thereof relates to acrystalline Netarsudil and salts thereof which does not include anycrystalline water (or other solvents) in a defined, stoichiometricamount within the crystal. Moreover, an “anhydrous” form does notcontain more than 1% (w/w) of either water or organic solvents asmeasured for example by TGA.

The present disclosure comprises a crystalline form of Netarsudilmesylate designated as form N1. The crystalline form N1 of Netarsudilmesylate can be characterized by data selected from one or more of thefollowing: a XRPD pattern having peaks at 5.8, 11.9, 17.8, 19.9 and 23.8degrees 2-theta±0.2 degrees 2-theta; a XRPD pattern as depicted in FIG.1; or combinations of these data.

Crystalline form N1 of Netarsudil mesylate may be further characterizedby the XRPD pattern having peaks at 5.8, 11.9, 17.8, 19.9 and 23.8degrees 2-theta±0.2 degrees 2-theta, and also having one, two, three orfour additional peaks at 6.8, 21.2, 24.5 and 26.6 degrees 2-theta±0.2degrees 2-theta; and combinations of these data.

Crystalline form N1 of Netarsudil mesylate may be characterized by eachof the above characteristics alone/or by all possible combinations,e.g., by XRPD pattern having peaks at 5.8, 11.9, 17.8, 19.9 and 23.8degrees 2-theta±0.2 degrees 2-theta and a XRPD pattern as depicted inFIG. 1.

Crystalline form N1 of Netarsudil mesylate is netarsudil:methanesulfonicacid 1:2.

The present disclosure comprises a crystalline form of Netarsudilmesylate designated as form N2. The crystalline form N2 of Netarsudilmesylate can be characterized by data selected from one or more of thefollowing: a XRPD pattern having peaks at 11.3 and 17.0 degrees2-theta±0.2 degrees 2-theta; a XRPD pattern as depicted in FIG. 2; orcombinations of these data.

Crystalline form N2 of Netarsudil mesylate is netarsudil:methanesulfonicacid 1:2, i.e. Netarsudil dimesylate.

The present disclosure comprises a crystalline form of Netarsudilmesylate designated as form N3. The crystalline form N3 of Netarsudilmesylate can be characterized by data selected from one or more of thefollowing: a XRPD pattern having peaks at 4.3, 8.5, 12.7, 14.8 and 17.0degrees 2-theta±0.2 degrees 2-theta; a XRPD pattern as depicted in FIG.3; or combinations of these data.

Crystalline form N3 of Netarsudil mesylate is netarsudil:methanesulfonicacid 1:2, i.e. Netarsudil dimesylate.

The present disclosure comprises a crystalline form of Netarsudilmesylate designated as form N4. The crystalline form N4 of Netarsudilmesylate can be characterized by data selected from one or more of thefollowing: a XRPD pattern having peaks at 5.4, 10.7, and 16.1 degrees2-theta±0.2 degrees 2-theta; a XRPD pattern as depicted in FIG. 4; orcombinations of these data.

The present disclosure comprises a crystalline form of Netarsudilmesylate designated as form N5. The crystalline form N5 of Netarsudilmesylate can be characterized by data selected from one or more of thefollowing: a XRPD pattern having peaks at 11.8, 13.2, 17.8, 18.9 and20.2 degrees 2-theta±0.2 degrees 2-theta; a XRPD pattern as depicted inFIG. 5; or combinations of these data.

Crystalline form N5 of Netarsudil mesylate may be further characterizedby the XRPD pattern having peaks at 11.8, 13.2, 17.8, 18.9 and 20.2degrees 2-theta±0.2 degrees 2-theta, and also having one, two, three,four or five additional peaks at 13.6, 18.1, 21.7, 23.3 and 24.9 degrees2-theta±0.2 degrees 2-theta; and combinations of these data.

Crystalline form N5 of Netarsudil mesylate may be characterized by eachof the above characteristics alone/or by all possible combinations,e.g., by XRPD pattern having peaks at 11.8, 13.2, 17.8, 18.9 and 20.2degrees 2-theta±0.2 degrees 2-theta and a XRPD pattern as depicted inFIG. 5.

Crystalline form N5 of Netarsudil mesylate is netarsudil:methanesulfonicacid 1:2, i.e. Netarsudil dimesylate.

The present disclosure comprises a crystalline form of Netarsudilmesylate designated as form N6. The crystalline form N6 of Netarsudilmesylate can be characterized by data selected from one or more of thefollowing: a XRPD pattern having peaks at 12.8, 14.3, 16.9, 18.6 and20.4 degrees 2-theta±0.2 degrees 2-theta; a XRPD pattern as depicted inFIG. 6; or combinations of these data.

Crystalline form N6 of Netarsudil mesylate may be further characterizedby the XRPD pattern having peaks at 12.8, 14.3, 16.9, 18.6 and 20.4degrees 2-theta±0.2 degrees 2-theta, and also having one, two, three,four or five additional peaks at 15.7, 20.8, 23.0, 24.4 and 25.3 degrees2-theta±0.2 degrees 2-theta; and combinations of these data.

Crystalline form N6 of Netarsudil mesylate may be characterized by eachof the above characteristics alone/or by all possible combinations,e.g., by XRPD pattern having peaks at 12.8, 14.3, 16.9, 18.6 and 20.4degrees 2-theta±0.2 degrees 2-theta and a XRPD pattern as depicted inFIG. 6.

The present disclosure comprises a crystalline form of Netarsudilmesylate designated as form N7. The crystalline form N7 of Netarsudilmesylate can be characterized by data selected from one or more of thefollowing: a XRPD pattern having peaks at 5.8, 11.5, 17.2, 19.0 and 21.5degrees 2-theta±0.2 degrees 2-theta; a XRPD pattern as depicted in FIG.7; or combinations of these data.

Crystalline form N7 of Netarsudil mesylate may be further characterizedby the XRPD pattern having peaks at 5.8, 11.5, 17.2, 19.0 and 21.5degrees 2-theta±0.2 degrees 2-theta, and also having one, two, three,four or five additional peaks at 13.9, 15.0, 16.5, 18.0 and 22.7 degrees2-theta±0.2 degrees 2-theta; and combinations of these data.

Crystalline form N7 of Netarsudil mesylate may be characterized by eachof the above characteristics alone/or by all possible combinations,e.g., by XRPD pattern having peaks at 5.8, 11.5, 17.2, 19.0 and 21.5degrees 2-theta±0.2 degrees 2-theta and a XRPD pattern as depicted inFIG. 7.

Crystalline form N7 of Netarsudil mesylate is netarsudil:methanesulfonicacid 1:2, i.e. Netarsudil dimesylate.

Crystalline form N7 is obtained as a white solid with high chemicalpurity with high factor purification of the (R)-isomer. Without wishingto be bound by any theory, netarsudil mesylate form N7 may comprisereduced amount of (R)-isomer by about 5-10 times compared to thestarting material(S)-4-(3-((tert-butoxycarbonyl)amino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl2,4-dimethylbenzoate, therefore the amount (S)-isomer would be higher.

The present disclosure further encompasses processes for preparingNetarsudil salts or solid state forms thereof. The process comprisespreparing the solid state form of the present disclosure, and convertingit to other Netarsudil salt and solid state forms thereof or other solidstate forms of the same salt. The conversion can be done, for example,by a process comprising reacting the obtained Netarsudil with anappropriate acid to obtain the corresponding acid addition salt.

The present disclosure further encompasses a pharmaceutical compositionor formulation prepared by combining the solid state form of the presentdisclosure and at least one pharmaceutically acceptable excipient.

In another embodiment the present disclosure encompasses the abovedescribed solid state forms of Netarsudil and salts thereof, for use inthe preparation of pharmaceutical compositions and/or formulations,preferably for the treatment of glaucoma or ocular hypertension.

In another embodiment the present disclosure encompasses the use of theabove described solid state forms of Netarsudil and salts thereof, orcombinations thereof, for the preparation of pharmaceutical compositionsand/or formulations, preferably for local treatment in a form ofophthalmic solution.

The present disclosure further provides pharmaceutical compositionscomprising the solid state forms of Netarsudil and salts thereof, orcombinations thereof, according to the present disclosure.

In yet another embodiment, the present disclosure encompassespharmaceutical formulations comprising at least one of the abovedescribed solid state forms of Netarsudil and salts thereof, and atleast one pharmaceutically acceptable excipient.

The present disclosure encompasses a process to prepare saidformulations of Netarsudil and salts thereof comprising combining atleast one of the above solid state forms and at least onepharmaceutically acceptable excipient.

The solid state forms as defined herein, as well as the pharmaceuticalcompositions or formulations of Netarsudil and salts thereof can be usedas medicaments, particularly for the treatment of glaucoma or ocularhypertension.

The present disclosure also provides a method of treating glaucoma orocular hypertension, comprising administering a therapeuticallyeffective amount of the solid state form of Netarsudil and salts thereofof the present disclosure, or at least one of the above pharmaceuticalcompositions or formulations, to a subject suffering from glaucoma orocular hypertension or otherwise in need of the treatment.

The present disclosure also provides the use of the solid state forms ofNetarsudil and salts thereof of the present disclosure, or at least oneof the above pharmaceutical compositions or formulations for themanufacture of a medicament for glaucoma or ocular hypertension.

Having described the invention with reference to certain preferredembodiments, other embodiments will become apparent to one skilled inthe art from consideration of the specification. The invention isfurther illustrated by reference to the following examples describing indetail the preparation of the composition and methods of use of theinvention. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced withoutdeparting from the scope of the invention.

Analytical Methods

X-Ray Powder Diffraction Method:

XRPD analysis was performed on ARL (SCINTAG) powder X-Ray diffractometermodel X'TRA equipped with a solid state detector. Copper radiation of1.5418 Å was used. Scanning parameters: range: 2-40 degrees two-theta;scan mode: continuous scan; step size: 0.05°, and a rate of 3 deg/min.

EXAMPLES

The starting materials Netarsudil base and(S)-4-(3-((tert-butoxycarbonyl)amino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl2,4-dimethylbenzoate can be prepared according to the U.S. Pat. No.8,394,826.

Example 1: Preparation of Netarsudil Mesylate Form N1

To a stirred solution of Netarsudil base (0.5 g, 1 eq) in isopropylalcohol (IPA) (2.5 mL, 5 vol), methanesulfonic acid (166.88 μL, 2.15 eq)was added. After few minutes a precipitate was obtained and the slurrymixture was stirred for 2 days at RT. The solid was filtered undernitrogen, washed with IPA and dried in vacuum oven at 50° C. over theweekend to give Netarsudil mesylate form N1. Netarsudil mesylate form N1has been confirmed by XRPD as presented in FIG. 1.

Netarsudil mesylate Form N1 is netarsudil:methanesulfonic acid 1:2 asconfirmed by analytical techniques such as ¹H-NMR and ¹³C-NMR.

Example 2: Preparation of Netarsudil Mesylate Form N2

To a solution of Netarsudil base (0.3 g, 1 eq) in 2-butanol (3.3 ml, 11vol) under nitrogen atmosphere, a solution of methanesulfonic acid (100μL, 2.15 eq) in diethyl ether (1 mL) was added dropwise using syringepump (10 μL/min.) at 0° C. A precipitate was obtained and the slurrymixture was stirred for 2 days at 0° C. The solid was filtered undernitrogen, washed with 2-butanol and dried in vacuum oven at 50° C. overthe weekend to give Netarsudil mesylate form N2. Netarsudil mesylateform N2 has been confirmed by XRPD as presented in FIG. 2.

Example 3: Preparation of Netarsudil Mesylate Form N3

Netarsudil mesylate Form N1 (50 mg) was placed in a plastic tube andinserted to a vial filled with 2 ml of BuOH (n-butanol). The vial wastightly closed for 1 week and after 1 week to give Netarsudil mesylateform N3. Netarsudil mesylate form N3 has been confirmed by XRPD aspresented in FIG. 3.

Example 4: Preparation of Netarsudil Mesylate Form N4

Netarsudil mesylate Form N1 (50 mg) was placed in a plastic tube andinserted to a vial filled with 2 ml of ethanol. The vial was tightlyclosed for 1 week to give Netarsudil mesylate form N4. Netarsudilmesylate form N4 has been confirmed by XRPD.

Example 5: Preparation of Netarsudil Mesylate Form N4

Netarsudil mesylate Form N1 (50 mg) was placed in a plastic tube andinserted to a vial filled with 2 ml of toluene. The vial was tightlyclosed for 1 week and after 1 week to give Netarsudil mesylate form N4.Netarsudil mesylate form N4 has been confirmed by XRPD.

Example 6: Preparation of Netarsudil Mesylate Form N4

Netarsudil mesylate Form N1 (50 mg) was placed in a plastic tube andinserted to a vial filled with 2 ml of 1-PrOH (1-Propanol). The vial wastightly closed for 1 week to give Netarsudil mesylate form N4.Netarsudil mesylate form N4 has been confirmed by XRPD as presented inFIG. 4.

Example 7: Preparation of Netarsudil Mesylate Form N5

Netarsudil mesylate Form N1 (50 mg) was placed in a plastic tube andinserted to a vial filled with 2 ml of Acetonitrile. The vial wastightly closed for 1 week to give Netarsudil mesylate form N5.Netarsudil mesylate form N5 has been confirmed by XRPD as presented inFIG. 5.

Example 8: Preparation of Netarsudil Mesylate Form N6

Netarsudil free base (1 eq) and 2-BuOH (11 vol) were charged in 250 mlreactor and the mixture was stirred under nitrogen atmosphere at RT togive an oily suspension. The reactor content was cooled to 0° C. and asolution of MSA (methanesulfonic acid) (2.15 eq) in diethyl ether (3.75vol) was added dropwise by a syringe pump (10 μL/min) under nitrogenatmosphere at 0° C. during 20 hr. A precipitate was obtained and theslurry mixture was stirred for 1 day at 0° C. The solid was filteredunder nitrogen, washed with 2-BuOH and dried in vacuum oven at 50° C.for 72 hr to give Netarsudil mesylate form N6. Netarsudil mesylate formN6 has been confirmed by XRPD as presented in FIG. 6.

Example 9: Preparation of Netarsudil Mesylate Form N7

Netarsudil mesylate Form N1 (50 mg) was placed in a plastic tube andinserted to a vial filled with 2 ml of iso-butanol. The vial was tightlyclosed for 1 week to give Netarsudil mesylate form N7. Netarsudilmesylate form N7 has been confirmed by XRPD as presented in FIG. 7.

Example 10: Preparation of Netarsudil Mesylate Form N3

To a stirred solution of(S)-4-(3-((tert-butoxycarbonyl)amino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl2,4-dimethylbenzoate (5.0 g 1 eq.) in DCM (dichloromethane) (10 vol),methanesulfonic acid (2.5 eq) was added dropwise. The reaction mixturewas stirred at room temperature over 15 h and completion of the reactionwas ascertained by HPLC. A gradual solvent switch from DCM to 2-BuOH wasthen carried out. The solution of the DCM solvent was removed bydistillation under vacuum. Next, two substantial portions of 2-BuOH wereadded to the residue follows by vacuum distillation. Eventually, 2-BuOH(10 vol) was added to the residue and the reaction mixture was stirredat room temperature over a period of 15 h.

The dimesylate salt was isolated as a solid by filtration undernitrogen. After washing with 2-BuOH (2×1 vol) and heptane (2×1 vol), thesolid was dried upon vacuum oven at 40° C. over 15 h. The compound wasobtained as a white solid (2.52 g). Netarsudil mesylate form N3 has beenconfirmed by XRPD.

Example 11: Preparation of Netarsudil Mesylate Form N7

To a stirred solution of(S)-4-(3-((tert-butoxycarbonyl)amino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl2,4-dimethylbenzoate (5.0 g 1 eq.) in DCM (dichloromethane) (10 vol),methanesulfonic acid (2.5 eq) was added dropwise. The reaction mixturewas stirred at room temperature over 4 h and completion of the reactionwas ascertained by HPLC. A gradual solvent switch from dichloromethaneto 2-BuOH was then carried out. The solution of the DCM solvent wasremoved by distillation under vacuum. Next, two substantial portions of2-BuOH were added to the residue follows by vacuum distillation.Eventually, 2-BuOH (10 vol) was added to the residue and the reactionmixture was stirred at room temperature over a period of 15 h.

The dimesylate salt was isolated as a solid by filtration undernitrogen. After washing with 2-BuOH (2×1 vol) and heptane (2×1 vol), thesolid was dried upon vacuum oven at 50° C. over 15 h. The compound wasobtained as a white solid (4.81 g, 99.9% purity and contained 0.10%(R)-isomer). Netarsudil mesylate form N7 has been confirmed by XRPD.

The invention claimed is:
 1. Crystalline form N7 of Netarsudil mesylatecharacterized by data selected from one or more of the following: (i) aPXRD pattern having peaks at 5.8, 11.5, 17.2, 19.0 and 21.5 degrees2-theta±0.2 degrees 2-theta; (ii) a PXRD pattern as depicted in FIG. 7;(iii) a PXRD pattern having peaks at 5.8, 11.5, 17.2, 19.0 and 21.5degrees 2-theta±0.2 degrees 2-theta, and also having one, two, three,four or five additional peaks at 13.9, 15.0, 16.5, 18.0 and 22.7 degrees2-theta±0.2 degrees 2-theta; and (iv) combinations of any of (i)-(iii).2. A pharmaceutical composition or formulation comprising crystallineform N7 of Netarsudil mesylate according to claim 1 and at least onepharmaceutically acceptable excipient.
 3. A pharmaceutical compositionor formulation prepared by combining the crystalline form N7 ofNetarsudil mesylate according to claim 1 and at least onepharmaceutically acceptable excipient.
 4. The pharmaceutical compositionor formulation according to claim 2 for local treatment in a form ofophthalmic solution.
 5. A process for preparing a pharmaceuticalcomposition or formulation according to claim 2 comprising combining acrystalline form N7 of Netarsudil mesylate according to claim 1, and atleast one pharmaceutically acceptable excipient.
 6. A process forpreparing a pharmaceutical composition or formulation of Netarsudil andsalts thereof comprising converting the crystalline form N7 ofNetarsudil mesylate according to claim 1 to Netarsudil or salt thereof;and combining Netarsudil or salt thereof with at least onepharmaceutically acceptable excipient.
 7. A method of treating glaucomaor ocular hypertension, comprising administering a therapeutic effectiveamount of crystalline form N7 of Netarsudil mesylate according to claim1 to a subject suffering from glaucoma or ocular hypertension.
 8. Amethod of treating glaucoma or ocular hypertension, comprisingadministering the pharmaceutical composition or formulation according toclaim 2 to a subject suffering from glaucoma or ocular hypertension. 9.A method of treating glaucoma or ocular hypertension, comprisingadministering the pharmaceutical composition or formulation according toclaim 3 to a subject suffering from glaucoma or ocular hypertension.